Alpha-phenylben-zoyl-alpha-arylaminocarbinol derivatives



United States Patent 3,018,305 a-PHENYLBEN-ZOYL-a-ARYLANHNOCARBINOLDERIVATIVES Guido Cavallini and Elena Massarani, Milan, Italy, as-

signors to Francesco Vismara S.p.A., Casatenovo, Italy, a firm NoDrawing. Filed July 6, 1959, Ser. No. 824,927 Claims priority,application Great Britain May 21, 1959 8 Claims. (Cl. 260-519) Thisinvention is concernedwith a new class of chemical compounds, namelya-phenylbenzoyl-a-arylaminocarbinol derivatives, having novel antiviralactivity and with synthetic methods for preparing such compounds.

More specifically, the new compounds of this invention have a verypronounced chemotherapeutic activity, particularly in various viralinfections such as distemper virus, influenza virus (PR8), hepatitisvirus (MHV neurotropic virus (CLM), Herpes simplex, adenovirus,Newcastle disease virus, Coxsackie virus, Echo virus and hemadsorptionvirus. Activity against the first four mentioned viral entities isexceptionally pronounced. Coupled with the chemotherapeutic activity ofthese compounds is a low order of toxicity.

The carbinol derivatives of this invention are represented by thefollowing basic general formula:

R dx

where R represents hydrogen, halogen such as chlorine, fluorine, orbromine, hydroxy, lower alkoxy of 1 to 4 carbon atoms inclusive, loweralkyl of 1 to 4 carbon atoms or benzyloxy.

R represents hydrogen or halogen such as chlorine, fluorine or bromine.

X represents hydrogen or a hydrocarbon radical of frorn'l to 12 carbonatoms inclusive.

Advantageous compounds of this invention are represented by thefollowing general formula:

I ox RI where 'R represents hydrogen, halogen of atomic weight less than80, hydroxy, methoxy or ethoxy,

R represents hydrogen or halogen of atomic weight less than 80, and

'X represents hydrogen, lower saturated or unsaturated aliphatichydrocarbon radical of l to 8 carbon atoms, in elusive, or benzyl.

Preferred compounds of this invention are represented by Formula H wheref R represents hydrogen, hydroxy or methoxy R represents hydrogen orchlorine X represents hydrogen or lower alkyl of from 1 to 8 carbonatoms.

Particularly preferred and advantageous compounds are those in which Rand R are hydrogen and X is hydrogen or lower alkyl particularly methylor ethyl.

The compounds of this invention are prepared by condensing either thealcoholate (hemiacetal) or hydrate addition compounds of abiphcnylglyoxal with an aminobenzoic acid with elimination of one moleof water. Specifically, approximately molar equivalent amounts of theaddition compound and the aminobenzoic acid in an inert organic solventin which the reactants are substantially soluble are reacted at fromabout room temperature i.e. about 25 C. up to the boiling point of thesolvent em- CODE MICE

ployed for periods of from about 15 minutes to about 24 hours. An excessof either reactant can be employed but with little advantage. Thereaction time can vary greatly depending on the reaction temperature aswell as the chemical nature of the reactants but reaction temperaturesoutside of those detailed here are usually of no particular advantage.Preferably the reaction time is from about /2 to 8 hours at temperaturesfrom about 40100 C. The organic solvent for preparing the etherderivatives is advantageously the alcohol corresponding to thealcoholate addition product involved; thus, for instance, if thealcoholate used as starting material is the methylate, it is advisableto use methyl alcohol as a reaction diluent. If an alcoholate is used,it is preferred to exclude water from the reaction medium. If a hydrateaddition compound is used as starting material for preparing a carbinol,non-alcoholic solvents, such as aryl solvents for instance benzene ortoluene, ethers or cycloalkane solvents are preferably used with alcoholbeing excluded. This latter restriction however is not a criticalrestriction on the method. The desired condensation product, a carbinolor its ether, is usually isolated by separating the crystallized solidby filtration following cooling. Alternatively the reaction solvent isremoved by evaporation and the residue purified by recrystallization.

The reaction is illustrated by the following reaction sequence.

COzH

The starting material biphenylglyoxal hydrate or alcoholate additioncompounds of Formula III in which R, R and X are as defined above areprepared by reacting the glyoxal with water or an alcohol, usually atroom or slightly elevated temperature such as up to about C. in asuitable solvent as mentioned above. For example, the alcoholates areobtained by reacting a biphenylglyoxal, anhydrous or hydrate, with analcohol under anhydrous conditions usually in an excess of the alcoholwith gentle heating at about 60 C. The glyoxal gradually goes intosolution. Cooling separates the desired alcoholate addition product.

Alternatively, the crystalline hydrate can be heated in an excess ofalcohol in an anhydrous state with removal of the water formed viaazeotropic distillation with a solvent such as benzene, xylene ortoluene to give the desired alcoholate.

Certain of the intermediate compounds of Formula 111 havechemotherapeutic activity, particularly anti-viral activity against theviruses noted above, in their own right in addition to their value asintermediates. Preferred are those in which R is p-hydroxy or alkoxy, Ris hydrogen or halo andX is lower alkyl or hydrogen. These compounds arethe subject of our copending application Serial No. 829,532, filed July27, 1959.

The substituted biphenylglyoxal starting materials are either known perse or are prepared from easily available phenylacetophenone derivativesby oxidation such as with selenium dioxide. The correspondingacetophenone compounds are generally well-known in the prior art. In therare instances in which they are not, a Friedel-Crafts acylation of asubstituted diphenyl with acetyl chloride under standard conditions iseasily carried out.

The new compounds of this invention can be used advantageously asprophylactic agents as well as chemotherapeutic drugs for both human andveterinary purposes in the treatment of viral infections and diseases.For example, the compounds of Formula II above where R and R arehydrogen and X is a lower alkyl or hydrogen give striking results in thecure of clinical distemper in dogs.

The drugs have proved to be active at very low doses (even somewhatlower than about 20 mg./kg.) while on the other hand their toxicitybecomes apparent at doses above 3000 mg./kg. The antiviral activityseems not to depend on the route of administration; therefore the newcompounds can be given both by oral or subcutaneous routes. Especiallyby the oral route as capsules, tablets or the like, the compounds areadministered as free acids combined with a pharmaceutical carrier. Ifthe subcutaneous route is chosen it is advisable to employ an ester or,better, a nontoxic salt With a pharmaceutically acceptable base in orderto facilitate the dissolution in the oily or aqueous vehicles ofadministration. In summary, therefore the compounds of this inventioncan be given to virus infected organisms or prophylactically to normal,exposed organisms either orally, intranasally or parenterally combinedwith an inert pharmaceutical carrier in an amount to cure or mitigatethe course of virus infection. The dose range for daily regimen will bewithin that mentioned here above, namely from 15 mg./kg. to about 3000mg./kg. depending on the size or species of animal.

The following examples will illustrate the novel aspects of thisinvention fully and enable one skilled in the art to practice thisinvention. Obviously other minor variations of this invention can beeasily designed such as using unsymmetrical biphenylglyoxals to give andpphenyl-benzoylarylaminocarbinols. Such variations are included in thescope of this invention.

Example 1 A mixture of 7.75 g. of selenium dioxide, 2 cc. of water and20 cc. of dioxan is heated to 70 C. while a solution of 11.13 g. of4-acetyl-4-methoxybiphenyl in 60 cc. of dioxan is added dropwise. Themixture is heated at reflux for 5 hours, then filtered hot and partiallyevaporated. Cooling separates 4'-methoxybiphenylyl-4-glyoxal hydrate,M.P. 136-137 C.

A mixture of 8.0 g. of the glyoxal in 100 cc. of absolute ethyl alcoholis heated at reflux for several hours. The clear solution is evaporatedslightly then cooled to give the desired ethylate, M.P. 119-120 C.

The ethylate (2.9 g.) and 1.45 g. of p-amino-benzoic acid in 50 cc. ofabsolute ethyl alcohol is heated at reflux for 5 hours. After slightevaporation, the solution is cooled to separate the desired ethyl etherof u-(p-4- methoxyphenylbenzoyl) a (4 carboxyphenylamino)- carbinol,M.P. 224 C. 4

The ethyl ether (500 mg.) is dissolved in water containing one molarequivalent of Sodium hydroxide. Evaporation gives the sodium salt.

Example 2 A mixture of 7.5 g. of anhydrous hiphenlyl-4-glyoxal in 60 cc.of anhydrous methyl alcohol is heated at 60 C. with stirring untilclear. Cooling separates the methylate, M.P. 9596 C.

A solution of 4.8 g. of the methylate and 2.8 g. of p. aminobenzoic acidin 60 cc. of methanol is heated at 60 C. for. 4 hours. Cooling separatedthe desired methyl ether of a-(p-phenylbenzoyl)-u(4-carboxyphenylamino)-carbinol, M.P. 192-194" C.

Example 3 This compound, 3.5 g., is reacted in 150 cc. of benzene with1.4 of p-aminobenzoic acid to give the desired noctyl ether ofa-(p-phenylbenzoyl)- z-(4-carboxy-phenylamino) carbinol, M.P. 134-136 C.

Example 4 A mixture of 3.7 g. of biphenylyl-4-glyoxal in 50 cc. ofanhydrous allyl alcohol is heated at 60 C. for several hours to give thedesired allylate, M.P. 93 C. This compound (2.7 g.) is reacted with 1.4g. of paminobenzoic acid as in Example 2 to give the desired allyl etherof c-(p-phenylbenzoyl)-a-(4-carboxyphenylamino)- carbinol, M.P. l92-194C.

Example 5 A mixture of 3.7 g. of biphenylyl-4-glyoxal and 30 cc. ofpropargyl alcohol in benzene is heated at reflux to give the desiredproparglyate, M.P. 97 C. This compound (2.6 g.) is reacted with 1.4 g.of p-aminobenzoic acid at 60 C. for 1 hour to give the propargyl etherof a (p phenylbenzoyl) a (4- carboxyphenylamino)- carbinol, M.P. 192-194C.

Example 6 A mixture of 1.8 g. of biphenylyl-4-glyoxal and 20 cc. ofisopropyl alcohol in benzene is reacted to give the desiredisopropylate, M.P. 93-94 C. which (2.7 g.) is reacted with 1.4 g. ofp-arninobenzoic acid as in Example 2 to give the isopropyl ether, M.P.192-194 C.

In similar manner, the n-butylate is formed, M.P. 54 C. and reacted witho-aminobenzoic acid to form the butyl ether ofa-(p-phenylbenzoyl)-a-(2-carboxyphenylamino)-carbinol as in Example 2.

Also the n-propylate is formed, M.P. 86-87 C., and reacted withm-aminobenzoic acid as in Example 2 to give the propyl ether ofa-(p-phenylbeuzoyl)-a-(3-carboxy-phenylamino) carbinol.

The ethylate is formed, M.P. 100-103 C., and reacted with an equimolaramount of p-aminobenzoic acid as in Example 2 to give the ethyl ether,M.P. 192-194 C.

Example 7 A mixture of 3.9 g. of selenium dioxide and 15 cc. of aqueousdioxan is reacted with 6.5 g. of 4'-acetyl-3-chlor0- 4-methoxybiphenyl(prepared by reacting acetyl chloride with 3-chloro-4-methoxybiphenylunder Friedel-Crafts conditions) in 40 cc. of dioxane as described inExample 1 to give the glyoxal as the hydrate, M.P. 141-142 C. Thiscompound (5.5 g.) is reacted with 2.8 g. of p-aminobenzoic acid inbenzene to give a(p-3-chloro-4-methoxyphenyl benzoyl) a (4carboxyphenylamino) carbinol after warming on the steam bath for 1 hour,M.P. 224-225 C.

Example 8 A mixture of 2.8 g. of the hydrate of 3'-chloro-4'-methoxyhiphenylyl-4-glyoxal is reacted with ethyl alcohol as in Example1 to give the ethylate addition compound, M.P. -87 C. This ether (3 g.)is reacted with 1.4 g. of p-aminobenzoic acid in absolute ethyl alcoholat 60 C. for 6 hours. Cooling separates the ethyl ether of a-(p-3-chloro 4 methoxyphenyl benzoyl) -m-(4-carboxyphenylamino)-carbinol,M.P. 228 C.

A small portion of the ether (200 mg.) is dissolved in dry dioxane andreacted with metallic potassium to separate the potassium salt.

Example 9 A solution of 4.5 g. of 4'-hydroxybiphenylyl-4-glyoxal in 50cc. of anhydrous ethyl alcohol is heated at reflux until clear.P-aminobenzoic acid (2.8 g.) is then added to the crude ethylatesolution and the heating period extended for several hours. Coolingseparated the ethyl ether of a- (p 4 hydroxyphenylbenzoyD-a-(4-carboxyphenylamino)-carbinol, M.P. 216217 C.

Example 10 A solution of 4.5 g. of 4'-chlorobiphenyly1-4-glyoxal in 50cc. of anhydrous methyl alcohol is heated at 60 C. for several hours togive the methylate. This compound (2.7 g.) is heated at reflux in 75 cc.of methyl alcohol for an hour with 1.4 g. of p-aminobenzoic acid.Cooling after evaporation gives the desired methyl ether of a(p-4-chloropheny1benzoyl) a (4-carboxyphenylamino) -carbinol.

Example 11 Example 12 A solution of 6.8 g. of biphenyly1-4-glyoxa1 inbenzene is reacted with 30 cc. of benzyl alcohol at reflux for 6 hours.After working up as in Example 3, the benzylate is obtained, M.P. 86 C.This compound (3.2 g.) is reacted in benzene with 1.4 g. ofp-aminobenzoic acid by heating briefly on the steam bath. The solidresidue is the benzyl ether ofa-(p-phenylbenzoyl)-a-(4-carboxyphenylamino)-carbinol, M.P. 184-186 C.

Example 13 A solution of 12.4 g. of 4-acetyl-4-tert.-butylbiphenyl(prepared by the reaction of acetyl chloride with 4-tert.-butylbiphenylunder Friedel-Crafts conditions) is heated with 7.8 g. of seleniumdioxide in dioxane for several hours as in Example 1. The free seleniumis separated by filtration and the glyoxal separated from the solvent.The glyoxal g.) is heated with 26 cc. of cyclohexanol in benzene as inExample 3 to give the cyclohexylate addition product. This compound isthen reacted with an equivalent amount of p-aminobenzoic acid in benzeneas in Example 1 to give the desired cyclohexyl ether ofa-(p-4-tert.-butylphenylbenzoyl)-11-(4-carboxy-phenylamino)-carbinol.

Example 14 A mixture of 11.4 g. of 4-acetyl-3'-chloro-2'-methylbiphenyl(prepared by the Friedel-Crafts reaction as in Example 7) and 7 g. ofselenium dioxide in dioxane is heated for several hours. The product,isolated as in Example 1, is 3' chloro-2'-methylbiphenylyl-4-glyoxal.This compound (5.5 g.) is heated in 75 cc. of methyl alcohol for severalhours then 2.8 g. of p-aminobenzoic acid is added to the alcoholicsolution of the methylate compound and the reflux period continued.Cooling the filtered solution gives the methyl ether of a-(p-3-chloro- 2methylphenylbenzoyl) a (4 carboxyphenylamino)- carbinol.

Example 15 A solution of 5.4 g. of 4'-benzyloxybiphenylyl-4-glyoxal(prepared by reacting 4-hydroxybiphenyl with benzyl chloride understandard alkylation conditions, acetylating under Friedel-Craftsconditions and oxidizing selenium dioxide as in Example 7) in 75 cc. ofethyl alcohol is heated at 60 C. for 5 hours. Then an equimolar amountof p-aminobenzoic acid is added to the ethylate while the heating isresumed. Concentration gives the desired product, the ethyl ether ofa-(p-4-benzyloxyphenylb enzoyl) -a- (4-carboxyphenylamino) -carbinol.

Example 16 A solution of 5.4 g. of 3', 4'-dichlorobiphenylyl-4- glyoxal(prepared by Friedel-Crafts reaction on 4acetyl- 3,4'-dichlorobiphenylfollowed by selenium dioxide oxidation in dioxan as in Example 1) in cc.of methyl alcohol is heated at 60 C. for 4 hours. The product whichcrystallizes upon evaporation and cooling is the methylate. Thiscompound (2.9 g.) is reacted in methyl alcohol with 1.4 g. ofp-aminobenzoic acid at reflux for 2 hours. Cooling separates the methylether of a-(p-3,4- dichloro phenylbenzoyl) cc 4- carboxyphenylamino)-carbinol.

Example 17 A solution of 3.7 g. of biphenylyl-Z-glyoxal is reacted with50 cc. of methyl alcohol and then with 2.5 g. of p-aminobenzoic acid asin Example 2 to give the methyl ether ofa-(o-phenylbenzoyl-u-(4-carboxyphenylamino)- carbinol.

Example 18 A mixture of 1.14 g. of biphenylyl-4-glyoxal hydrate with 50cc. of methyl alcohol and then with 2.5 g. of is gently boiled for 2hours, then cooled and filtered. The product isa-(p-phenylbenzoyl)-a-(4-carboxyphenyl amino)-carbinol, M.P. 197 C.

Example 19 A mixture of 2.4 g. of the methylate addition product ofbiphenylyl-4-glyoxal and 1.7 g. of ethyl p-aminobenzoate in 100 cc. ofmethyl alcohol is heated at reflux for several hours. Evaporation of thesolvent and cooling separates the methyl ether ofa-(p-phenylbenzoyD-a-(4- carbethoxyphenylarnino -carbinol.

Example 20 I C 02H l OX in which R is a member selected from the groupconsisting of hydrogen, halogen having an atomic weight less than 80,hydroxy, lower .alkoxy of l to 4 carbon atoms, lower alkyl of 1 to 4carbon atoms and benzyloxy; R is a member selected from the groupconsisting of hydrogen and halogen; and X is a member selected from thegroup consisting of hydrogen, an aliphatic hydrocarbon radical of '1 to12 carbon atoms and a monocyclic hydrocarbon radical containing no morethan 12 carbon atoms; and pharmaceutically acceptable alkali metal saltsof said acids.

2. A compound as claimed in claim 1 in which R is in 4'-position and Ris in the 3'-position.

3. A chemical compound having the following structural formula:

in which X is a lower alkyl of 1 to 8 carbon atoms.

COgH

a 5. A chemical compound having the following stmctural formula:

in which X is lower alkyl of 1 to 8 carbon atoms.

6. A chemical compound having the following structural formula:

COzH

7. A' chemical compound having the following structural formula:

8. The method of preparing carbinol derivatives having the followingstructural formula:

COzH

COzH

ing of hydrogen, halogen having an atomic weight less than 80, hydroxy,lower alkoxy of 1 to 4 carbon atoms, lower alkyl of l to 4 carbon atomsand benzyloxy; R is a member selected from the group consisting ofhydrogen and halogen; and X is a member selected from the groupconsisting of hydrogen, an aliphatic hydrocarbon radical of 1 to 12carbon atoms and a monocyclic hydrocarbon radical containing no morethan 12 carbon atoms, said method comprising reacting a biphenylylglyoXal addition product having the following structural formula:

R OH {1 AX in which R, R and X are as defined hereabove with anaminobenzoic acid in an inert organic solvent at reaction temperaturesof from about room temperature up to the boiling point of said organicsolvent.

References Cited in the file of this patent UNITED STATES PATENTS BambasFeb. 27, 1951 OTHER REFERENCES Musante et al.: Chem. Abst., vol. 46(1952), col. 4502-04.

1. A CHEMICAL COMPOUND SELECTED FROM THE GROUP CONSISTING OF AN ACIDHAVING THE FORMULA: